Synthesis of 1,2,3-triazole elements in histamine H3 receptor ligands

Article abstract of DOI:10.1055/s-0030-1260103

1,2,3-Triazole moieties were introduced in a histamine H₃ receptor antagonist pharmacophore blueprint with a versatile click chemistry approach, yielding potent ligands. Azide and alkynes were combined under copper(I) catalysis to provide the t

Full text of DOI:10.1055/s-0030-1260103

SPECIAL TOPIC
2733
Synthesis of 1,2,3-Triazole Elements in Histamine H3 Receptor Ligands
1,2,3-Triazoles in
H
istiamine 3
H
r
Recep
i
tor
L
ig
a
ands m Walter, Tim Kottke, Lilia Weizel, J. Stephan Schwed, Holger Stark*
Johann Wolfgang Goethe University, Institute of Pharmaceutical Chemistry, Biocenter, ZAFES/OSF/NeFF/CMP/ICNF,
Max-von-Laue-Str. 9, 60438 Frankfurt, Germany
Fax +49(69)79829352; E-mail: h.stark@pharmchem.uni-frankfurt.de
Received 25 February 2011
So far, different azole moieties have been successfully in-
troduced in hH3R ligands.4 Due to their favorable physico-
chemical properties, triazoles are highly recommended in
drug discovery. Huisgen’s 1,3-dipolar cycloaddition de-
Abstract: 1,2,3-Triazole moieties were introduced in a histamine
H3 receptor antagonist pharmacophore blueprint with a versatile
click chemistry approach, yielding potent ligands. Azide and
alkynes were combined under copper(I) catalysis to provide the tri-
azole element. Conventional synthesis, as well as microwave irradi- scribes the synthesis of 1,2,3-triazoles by the reaction of
azides and alkynes.5 Despite their high energy, azides and
ation, was successfully applied.
alkynes belong to the least reactive functional groups,
leading to inefficient reaction times and low yields. Cop-
per(I) catalysis enables an easy introduction of the tri-
azoles in a multitude of molecules, which makes this
reaction highly applicable in compound variations for
drug development.6,7
Key words: azides, alkynes, copper catalysis, click chemistry, his-
tamine H3 receptor
In the central nervous system (CNS), the human histamine
H3 receptor (hH3R) controls histamine-mediated neuro-
transmission. Its autoreceptor function and cross-linking
to other neurotransmitter systems via heteroreceptors play
a central role in maintaining the neurotransmitter bal-
ance.1 Due to the resulting modulation of numerous
(patho)physiological brain functions, such as vigilance,
memory processes and food intake, the H3R might be an
attractive target for the therapy of a multitude of CNS dis-
orders.2
Using this click chemistry approach on H3R antagonists,
we identified 1,2,3-triazole moieties as suitable structural
elements on the eastern part of the H3R antagonist con-
struction pattern, but these were insufficient as a linking
element (X, cf. Figure 1).8 Based on these findings, the
aim of the present work was the structural variation of the
1,2,3-triazole moiety in the eastern part of the molecule by
using polar alkynes (Figure 1). The influence of different
polar substituents on the binding behavior towards the re-
ceptor was easily evaluated. The hH3R affinities were de-
termined in a radioligand competitive binding assay,
described previously.9,10
The common pharmacophore blueprint of H3R antago-
nists/inverse agonists offers an amine moiety in the west-
ern part of the molecule linked by an alkyl spacer to a
mostly lipophilic central core structure. This receptor-
targeting part can be substituted by a broad range of struc-
tural elements, defining the activity of the compound
(Figure 1).3
The cycloaddition of azide and alkynes under copper(I)
catalysis was used for the synthesis of compounds 2–4
(Scheme 1).7,11 First, the H3R core fragment was prepared
according to the literature.12 The azide functionality was
incorporated using sodium azide in N,N-dimethylform-
amide. The resulting 1-{3-[4-(azidomethyl)phenoxy]pro-
pyl}piperidine (1) was used as a versatile precursor for the
click chemistry reaction performed with different alkynes
(namely, prop-2-yn-1-ol, propiolic acid and methyl propi-
olate), in a mixture of N,N-dimethylformamide and water
or isopropyl alcohol and water as solvent.8 Copper(I),
which was obtained in situ by reduction of copper(II) sul-
fate with sodium ascorbate, enabled the 1,3-dipolar cy-
cloaddition by forming copper acetylides, activating the
azide.11 The alcohol-containing derivative 2 and the ester
compound 4 were obtained by conventional synthesis in a
round-bottom flask upon stirring at room temperature.
Microwave irradiation was used for the preparation of
acid derivative 3.13
western part
eastern part
polar group
2nd basic moiety
lipophilic residue
acidic element
1st
basic
moiety
central
core
alkyl
spacer
X
R
N
N
O
N
N
X = linking element
Figure 1 Structural blueprint of H3R antagonists3 and general phar-
macophore of presented ligands
Compound 5 was obtained by an alternative method
(Scheme 1).14 The conventional cycloaddition of azide
derivative 1 and vinyl acetate was performed under micro-
wave conditions without catalysis.
SYNTHESIS 2011, No. 17, pp 2733–2736
Advanced online publication: 08.07.2011
DOI: 10.1055/s-0030-1260103; Art ID: C22611SS
x
x.
x
x
.
2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

2734
M. Walter et al.
SPECIAL TOPIC
Table 1 In Vitro Binding Affinities of Compounds 1–5 on hH3R
Compound
Chemical formula
C15H22N4O·(COOH)2
C18H26N4O2
Molecular weight (g/mol)
hH3R Kia [nM], (n)
28 0.6 (2)
8.7 0.1 (2)
1
2
3
4
5
364.41
330.42
344.41
358.43
435.46
C18H24N4O3
432 27 (2)
17 4.2 (2)
30 12 (4)
C19H26N4O3
C17H24N4O·1.5(COOH)2
a [3H]Na-Methylhistamine competitive binding assay on HEK-293 cells stably expressing hH3R;9 Kd = 2.98 nM;10 values are means SD of
two to four independent experiments performed at least in duplicate (number of experiments in parentheses).
All chemicals were obtained from Sigma-Aldrich, ABCR and
a
N
N
O
O
Acros Organics, and were used without further purification. Precur-
sor 1-{3-[4-(chloromethyl)phenoxy]propyl}piperidine was ob-
tained according to the literature.12 Melting points were determined
on a Büchi 510 melting point apparatus (Büchi, Switzerland) and
are uncorrected. 1H NMR spectra were recorded on a Bruker AMX
250 (250 MHz) or AV 300 (300 MHz) spectrometer (Bruker, Ger-
many). 1H NMR data are reported in the following order: chemical
shift (d) in ppm relative to TMS as internal reference; multiplicity
(s, singlet; d, doublet; t, triplet; m, multiplet); approximate coupling
constants (J) in hertz (Hz); number and assignment of protons (ox,
Cl
N
b or c
+
1
N
–
N
oxalate; ph, phenyl; pip, piperidine; prop, propyl; trz, triazole). 13
C
R
N
O
2 R = CH2OH
3 R = COOH
4 R = COOMe
5 R = H
NMR spectra were recorded on a Bruker AV 300 (75 MHz) spec-
trometer (Bruker, Germany). DMSO-d6 was used as the solvent.
ESI-MS was performed on a Fisons Instruments VG Platform II
spectrometer (Manchester, Great Britain) in positive polarity. Data
are listed as mass number ([M + H]+) and relative intensity (%). El-
emental analyses (C, H, N) were measured on a CHN-Rapid analyz-
er (Heraeus, Germany) and are within 0.4% of the theoretical
values for all final compounds. Preparative column chromatogra-
phy was performed on silica gel (63–200 mM; Merck, Germany).
Flash chromatography was carried out on Varian SuperFlash silica
gel (50 mM). TLC was performed on Merck plastic-backed silica gel
plates (DC-Plastikfolien 60, F254; layer thickness: 0.2 mm) that
were visualized with UV light (254 nm) or by staining with ninhy-
drin solution. Microwave irradiation was conducted in a Biotage
Initiator 2.0 microwave reactor (Biotage, Sweden).
N
N
N
2–5
Scheme 1 Preparation of 1–5. Reagents and conditions: (a) NaN3,
DMF, microwave (MW), 120 °C, 40 min, 98%; (b) Compounds 2 and
4: prop-2-yn-1-ol or methyl propiolate, CuSO4, sodium ascorbate,
DMF–H2O (2:1), r.t., 16 h, 2: 64%, 4: 42%; compound 3: propiolic
acid, CuSO4, sodium ascorbate, i-PrOH–H2O (1:1), MW, 125 °C, 10
min, 48%; (c) Compound 5: vinyl acetate, MW, 120 °C, 18 h, 26%.
All compounds prepared offered a good to excellent bind-
ing behavior to hH3R in the nanomolar concentration
range (Table 1). Compared to the unsubstituted 1,2,3-tria-
zole (compound 5) with a Ki value of 30 nM, an additional
alcohol or ester structure enhances affinity (Ki values of
8.7 nM and 17 nM, respectively). Introduction of the acid-
ic element in carboxylic acid 3 decreases receptor binding
(Ki value of 432 nM). This impairment most likely dem-
onstrates a limitation of the substitution pattern in the
eastern part of the hH3R antagonist blueprint for ionic el-
ements.
1-{3-[4-(Azidomethyl)phenoxy]propyl}piperidine (1)
1-{3-[4-(Chloromethyl)phenoxy]propyl}piperidine12 (1.2 g, 4.48
mmol) and NaN3 (0.641 g, 9.86 mmol) in DMF (8 mL) was placed
in a 10–20 mL vial. The reaction mixture was stirred with a magnet-
ic stirrer bar and subjected to microwave irradiation at 120 °C for
40 min. The mixture was diluted with 2 N aq NaOH (50 mL). The
aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The organic
layers were combined, dried (Na2SO4) and filtered. The solvent was
evaporated to dryness. Azide 1 was obtained as a brown oil; yield:
1.06 g (86%).
In summary, the click chemistry approach offers an ad-
vantageous synthetic way for the incorporation of 1,2,3-
triazoles in the H3R pharmacophore. Copper(I) catalysis
enables shorter reaction times, especially in the micro-
wave approach (compound 3), and higher yields com-
pared to the alternative cycloaddition (compound 5).
Whereas lipophilic alkynes have been preferred in the lit-
erature for 1,3-dipolar cycloreactions, we have success-
fully transferred the synthetic procedure to polar
structures, leading to high affine H3R antagonists/inverse
agonists.
Crystallization as the salt of oxalic acid led to a white solid; mp
177.7 °C.
Rf = 0.77 (CH2Cl2–ammoniacal MeOH, 9:1).
1H NMR (250 MHz, DMSO-d6): d = 7.28 (d, J = 8.6 Hz, 2 H, ph-
3,5H), 6.97 (d, J = 8.6 Hz, 2 H, ph-2,6H), 4.35 (s, 2 H, CH2N3), 4.04
(t, J = 6.0 Hz, 2 H, prop-3H2), 3.15–3.10 (m, 6 H, pip-2,6H2, prop-
1H2), 2.13–2.06 (m, 2 H, prop-2H2), 1.72–1.70 (m, 4 H, pip-3,5H2),
1.53 (m, 2 H, pip-4H2).
13C NMR (75 MHz, DMSO-d6): d = 164.32 (ox-COOH), 158.17
(ph-1C), 130.10 (ph-3,5C), 127.69 (ph-4C), 114.60 (ph-2,6C),
Synthesis 2011, No. 17, 2733–2736 © Thieme Stuttgart · New York

SPECIAL TOPIC
1,2,3-Triazoles in Histamine H3 Receptor Ligands
2735
65.00 (prop-3C), 53.45 (prop-1C), 53.13 (CH2N3), 52.16 (pip-
2,6C), 23.50 (prop-2C), 22.66 (pip-3,5C), 21.45 (pip-4C).
Methyl 1-[4-(3-Piperidin-1-ylpropoxy)benzyl]-1H-1,2,3-tri-
azole-4-carboxylate (4)
In a 100 mL round-bottomed flask, azide 1 (1.0 g, 3.64 mmol),
CuSO4 (0.291 g, 1.822 mmol) and sodium ascorbate (0.361 g, 1.822
mmol) were dissolved in DMF–H2O (2:1, total: 15 mL). Methyl
propiolate (0.457 mL, 5.47 mmol) was added under ice cooling and
argon atmosphere. The reaction mixture was stirred with a magnetic
stir bar at r.t. overnight. The residue was filtered off and the solution
was diluted with 2 N NaOH (pH 10, 50 mL). The aqueous layer was
extracted with EtOAc (3 × 70 mL). The organic layers were com-
bined, dried (Na2SO4) and filtered. The solvent was evaporated to
dryness. The residue was heated with EtOH (10 mL) at 80 °C for 30
min, and the product was collected by filtration. Ester 4 was ob-
tained as a white solid; yield: 550 mg (42%).
ESI-MS: m/z (%) = 275.2 (100) [M + H]+.
Anal. Calcd for C15H22N4O·(COOH)2: C, 56.03; H, 6.64; N, 15.37.
Found: C, 55.78; H, 6.55; N, 15.21.
{1-[4-(3-Piperidin-1-ylpropoxy)benzyl]-1H-1,2,3-triazol-4-
yl}methanol (2)
In a 100 mL round-bottomed flask, azide 1 (1 g, 3.64 mmol), CuSO4
(0.291 g, 1.822 mmol) and sodium ascorbate (0.361 g, 1.822 mmol)
were dissolved in DMF–H2O (2:1, total: 30 mL). Prop-2-yn-1-ol
(0.307 g, 5.47 mmol) was added under ice cooling and argon atmo-
sphere. The reaction mixture was stirred with a magnetic stir bar at
r.t. overnight. The residue was filtered off and the solution was di-
luted with 2 N NaOH (80 mL). The aqueous layer was extracted
with EtOAc (3 × 100 mL). The organic layers were combined, dried
(Na2SO4) and filtered. The solvent was evaporated to dryness. The
crude product was added to a silica gel column and eluted with
CH2Cl2–ammoniacal MeOH (99:1 to 9:1). Alcohol 2 was obtained
as a white solid; yield (crude product): 770 mg (64%).
Mp 126 °C; Rf = 0.38 (CH2Cl2–ammoniacal MeOH, 9:1).
1H NMR (250 MHz, DMSO-d6): d = 8.85 (s, 1 H, trz-5H), 7.30 (d,
J = 10.0 Hz, 2 H, ph-2,6H), 6.95 (d, J = 10.0 Hz, 2 H, ph-3,5H),
5.57 (s, 2 H, CH2-trz), 3.98 (t, J = 6.3 Hz, 2 H, prop-1H2), 3.83 (s, 3
H, OCH3), 2.38–2.25 (m, 6 H, pip-2,6H2, prop-3H2), 1.89–1.78 (m,
2 H, prop-2H2), 1.48–1.46 (m, 4 H, pip-3,5H2), 1.39–1.37 (m, 2 H,
pip-4H2).
13C NMR (75 MHz, DMSO-d6): d = 160.62 (COOCH3), 158.63
(ph-4C), 138.68 (trz-4C), 129.68 (ph-2,6C), 128.85 (ph-1C), 127.22
(trz-5C), 114.64 (ph-3,5C), 65.93 (prop-1C), 55.05 (prop-3C),
54.06 (pip-2,6C), 52.65 (CH2-trz), 51.73 (CH3), 26.18 (prop-2C),
25.54 (pip-3,5C), 24.09 (pip-4C).
Mp 96 °C; Rf = 0.67 (CH2Cl2–ammoniacal MeOH, 9:1).
1H NMR (300 MHz, DMSO-d6): d = 8.01 (s, 1 H, trz-5H), 7.32 (d,
J = 9.0 Hz, 2 H, ph-2,6H), 6.99 (d, J = 9.0 Hz, 2 H, ph-3,5H), 5.53
(s, 2 H, CH2-trz), 5.21 (br s, 1 H, OH), 4.54 (s, 2 H, CH2OH), 4.03
(t, J = 6.0 Hz, 2 H, prop-1H2), 2.48–2.40 (m, 6 H, pip-2,6H2, prop-
3H2), 1.97–1.86 (m, 2 H, prop-2H2), 1.57–1.53 (m, 4 H, pip-3,5H2),
1.34–1.30 (m, 2 H, pip-4H2).
ESI-MS: m/z (%) = 359.1 (100) [M + H]+.
13C NMR (75 MHz, DMSO-d6): d = 158.56 (ph-4C), 148.34 (trz-
4C), 129.55 (ph-2,6C), 128.27 (ph-1C), 122.43 (trz-5C), 114.59
(ph-3,5C), 65.87 (prop-1C), 55.01 (CH2-trz), 54.95 (prop-3C),
53.83 (pip-2,6C), 52.37 (CH2OH), 26.09 (prop-2C), 25.36 (pip-
3,5C), 23.72 (pip-4C).
Anal. Calcd for C19H26N4O3: C, 63.67; H, 7.31; N, 15.63. Found: C,
63.45; H, 7.37; N, 15.53.
1-{3-[4-(1H-1,2,3-Triazol-1-ylmethyl)phenoxy]propyl}piperi-
dine (5)
Azide 1 (0.75 g, 2.73 mmol) was placed in a 2–5 mL vial and excess
vinyl acetate (5 mL, 54.2 mmol) was added. The reaction mixture
was stirred with a magnetic stir bar and subjected to microwave ir-
radiation at 120 °C for 18 h. The mixture was concentrated and the
crude product was purified by flash chromatography (CH2Cl2–
ammoniacal MeOH, 99:1 to 9:1). The resulting brown oil [yield:
214 mg (26%)] was crystallized as the salt of oxalic acid, which was
obtained as a white solid; mp 104 °C.
ESI-MS: m/z (%) = 331.0 (100) [M + H]+.
Anal. Calcd for C18H26N4O2: C, 65.43; H, 7.93; N, 16.96. Found: C,
65.23; H, 7.87; N, 16.96.
1-[4-(3-Piperidin-1-ylpropoxy)benzyl]-1H-1,2,3-triazole-4-car-
boxylic Acid (3)
CuSO4 (0.7 mg, 0.073 mmol) and sodium ascorbate (11.90 mg,
0.073 mmol) in H2O (1.5 mL) was added to a 2–5-mL vial. Azide 1
(200 mg, 0.729 mmol) suspended in i-PrOH (1.5 mL) was added.
The mixture was aerated with argon and the vial was locked. Pro-
piolic acid (0.067 mL, 1.093 mmol) was added to the vial via sy-
ringe. The reaction mixture was stirred with a magnetic stir bar and
subjected to microwave irradiation at 125 °C for 10 min. The mix-
ture was concentrated to dryness. The crude product was added to a
silica gel column and eluted with CH2Cl2–ammoniacal MeOH
(2:1). Acid 3 was obtained as a light brownish solid; yield: 120 mg
(48%).
Rf = 0.74 (CH2Cl2–ammoniacal MeOH, 9:1).
1H NMR (250 MHz, DMSO-d6): d = 8.15 (br s, 1 H, trz-4H), 7.73
(br s, 1 H, trz-5H), 7.27 (d, J = 10.05 Hz, 2 H, ph-3,5H), 6.96 (d,
J = 10.05 Hz, 2 H, ph-2,6H), 5.54 (s, 2 H, CH2-trz), 4.03 (t, J = 6.25
Hz, 2 H, prop-3H2), 3.18–3.12 (m, 6 H, pip-2,6H2, prop-1H2), 2.17–
2.06 (m, 2 H, prop-2H2), 1.74 (m, 4 H, pip-3,5H2), 1.55 (m, 2 H, pip-
4H2).
13C NMR (75 MHz, DMSO-d6): d = 163.39 (ox-COOH), 158.04
(ph-1C), 133.44 (trz-5C), 129.47 (ph-3,5C), 128.45 (ph-4C), 124.61
(trz-4C), 114.66 (ph-2,6C), 64.99 (prop-3C), 53.36 (CH2-trz), 52.10
(prop-1C), 52.08 (pip-2,6C), 23.37 (prop-2C), 22.53 (pip-3,5C),
21.32 (pip-4C).
Mp 192 °C; Rf = 0.35 (CH2Cl2–ammoniacal MeOH, 2:1).
1H NMR (250 MHz, DMSO-d6): d = 8.41 (s, 1 H, trz-5H), 7.28 (d,
J = 8.6 Hz, 2 H, ph-2,6H), 6.93 (d, J = 8.6 Hz, 2 H, ph-3,5H), 5.51
(s, 2 H, CH2-trz), 3.97 (t, J = 6.4 Hz, 2 H, prop-1H2), 2.46–2.43 (m,
6 H, pip-2,6H2, prop-3H2), 1.90–1.82 (m, 2 H, prop-2H2), 1.54–
1.50 (m, 4 H, pip-3,5H2), 1.41–1.39 (m, 2 H, pip-4H2).
13C NMR (75 MHz, DMSO-d6): d = 162.87 (COOH), 158.40 (ph-
4C), 143.19 (trz-4C), 129.61 (ph-2,6C), 127.78 (ph-1C), 127.36
(trz-5C), 114.62 (ph-3,5C), 65.64 (prop-1C), 54.26 (prop-3C),
53.10 (pip-2,6C), 52.37 (CH2-trz), 25.01 (prop-2C), 24.27 (pip-
3,5C), 23.07 (pip-4C).
ESI-MS: m/z (%) = 301.1 (100) [M + H]+.
Anal. Calcd for C17H24N4O·1.5(COOH)2: C, 55.17; H, 5.87; N,
12.87. Found: C, 54.94; H, 6.04; N, 12.93.
Acknowledgment
This work was partially supported by the COST Action BM0806
‘Recent Advances in Histamine Receptor H4R Research’, the Else
Kröner-Fresenius-Stiftung, and the Hesse LOEWE projects OSF
and NeFF.
ESI-MS: m/z (%) = 345.1 (100) [M + H]+.
Anal. Calcd for C18H24N4O3: C, 62.77; H, 7.02; N, 16.27. Found: C,
62.47; H, 7.32; N, 16.01.
Synthesis 2011, No. 17, 2733–2736 © Thieme Stuttgart · New York

2736
M. Walter et al.
SPECIAL TOPIC
Timmerman, H.; Talaga, P.; Leurs, R.; Provins, L.
ChemMedChem 2009, 4, 1063. (f) Walter, M.; von Coburg,
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Schwartz, J. C.; Stark, H. Bioorg. Med. Chem. Lett. 2010, 20,
5879. (g) Walter, M.; Isensee, K.; Kottke, T.; Ligneau, X.;
Camelin, J. C.; Schwartz, J. C.; Stark, H. Bioorg. Med.
Chem. Lett. 2010, 20, 5883.
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